1. Field of the Invention
The present invention relates to a pharmaceutical composition for treating a heart disease which comprises diadenosine 5',5'"-P.sup.1, P.sup.4 -tetraphosphate as an active ingredient and to a method for treating a subject having a heart disease which comprises administering the pharmaceutical composition to the subject. More particularly, it relates to the pharmaceutical composition having antiarrhythmic and coronary vasodilative activities.
2. Description of the Prior Art
There tends to be a gradual increase in morbidity rate for cardiovascular diseases such as heart disease, arteriosclerosis and hypertension, as the number of the aged people increases and western-style dietary life becomes popular. Particularly, mortality from heart disorders ranks next to that from cancer, thus being one of the social problems. Cardiac disorders commonly include arrhythmia, heart failure, angina pectoris, coronary atherosclerosis, myocardial infarction, etc. Drugs for treating these disorders may be classified accordingly into antiarrhythmic agents, cardiotonics, coronary vasodilators, and so forth.
Arrhythmia arises from abnormalities in the rhythm of cardiac beat which should normally proceed at a regular pace, in particular an abnormality in the generation of spontaneous impulse in the sinoatrial node and an abnormality in the conduction system. It is classified into tachyarrhythmia and bradyarrhythmia according to frequency of the rhythm of cardiac beat.
Drugs for treatment of arrhythmia include the following groups: sodium ion channel inhibitors which exert an antirrhythmic effect by inhibiting the conduction system in the His bundle, Purkinje fibers, atrium, or ventricular muscle, through an electrophysiological mechanism; .beta.-blockers which indirectly inhibit the calcium ion channels in myocardial cell membranes, thus being effective in a treatment of the arrhythmia which arises from sympathicotonia or of the supraventricular arrhythmia in which the sinoatrial node and/or the atrioventricular node take part; drugs which exert an antiarrhythmic effect by prolonging a duration of action potential in all myocardial cells with the associated prolongation of refractory period and without the inhibition of sodium ion channel; calcium antagonists which exert an antiarrhythmic effect by inhibiting calcium ion channels in the myocardial cell membranes through the suppression of a slow response based on a slow inward calcium current; and other drugs such as digitalis and adenosine [Vaughan Williams, E. M., J. Clin. Pharmacol., 24, 129 (1984)].
Adenosine 5'-triphosphate (ATP), like adenosine, is known to possess the antiarrhythmic activity [Somlo, E., Lancet, 268, 1125 (1955); and Komor, K. and Garas, Z., Lancet, 269, 93 (1955)] and has now attracted attention owing to its potential as a new drug for treating arrhythmia. Such application of ATP is known to impart the following advantages: successful arrest of the paroxysmal supraventricular tachycardia; shorter time required for onset of the clinical effect of ATP, successively increasable dosage, and efficacy against the paroxysmal supraventricular tachycardia which is insusceptible to other antiarrhythmic drugs such as verapamil, digoxin and ajimaline [Otsuka, F., Kagoshima, T. and Ishikawa, H., Yakkyoku, 37(4), 25-28 (1986)].
Other heart diseases, for example, coronary atherosclerosis, myocardial infarction and angina pectoris, have been reported to arise from a diminished coronary blood flow. The coronary blood flow is affected by direct actions on coronary vessels of coronary vasomodulators such as adenosine, prostaglandins, cyclic AMP, noradrenaline, adrenaline and acetylcholine, or by indirect actions via variations of myocardial contractility, heart rate and blood pressure.
Therefore, the following coronary vasodilators which increase the coronary blood flow by dilating the coronary vessels are conventionally known: nitrites, substances for enhancing the activity of adenosine, calcium antagonists and phosphodiesterase inhibitors [Nakagawa, Y., Yakkyoku, 40(1), 245-253 (1989)]. Among them, the substances for enhancing the activity of adenosine which is considered to be a modulator of the coronary circulation give rise to a dilatation of coronary vessels and/or a formation of collateral vessels by enhancing its activity [Berne, R. M., Circ. Res., 47, 807-813 (1980)].
ATP has been reported to show some pharmacological effects, for example, vasodilation [Fujii, M. and Nakamura, M., Jap. Heart J., 18, 132 (1977)], enhancement of in vivo metabolic activity, increase in muscle contraction, and rise of efficiency of the neural transmission, as well as the aforementioned antiarrhythmic effect. As described below, however, the inventors found that ATP itself has platelet-aggregating activity. ATP may eventually bring the risk of increasing a blood viscosity, thereby causing a disturbance in the myocardial microcirculation. Accordingly, the use of ATP as a drug for treatment of heart diseases would be unadvisable and rather should be restricted in view of the above disturbance.
One object of the present invention is to provide a highly potent pharmaceutical composition for treating a heart disease, which is capable of replacing ATP and which is endowed with coronary vasodilative activity and antiplatelet activity as well as ATP-like antiarrhythmic activity.
Another object of the present invention is to provide a method for treating a subject having a heart disease which comprises administering said pharmaceutical composition to the subject.